Cancer immunotherapy has shifted the paradigm in cancer therapy by revitalizing immune responses against tumor cells. Specifically, in primary tumors cancer cells evolve in an immunosuppressive microenvironment, which protects them from immune attack. However, during tumor progression, some cancer cells leave the protective tumor mass, disseminating and seeding secondary organs. These initial disseminated tumor cells (DTCs) should potentially be susceptible to recognition by the immune system in the new host tissues. Although Natural Killer or T cells eliminate some of these DTCs, a fraction escape anti-tumor immunity and survive, thus giving rise to metastatic colonization. How DTCs interact with immune cells and the underpinnings that regulate imperfect immune responses during tumor dissemination remain poorly understood. Uncovering such mechanisms of immune evasion may contribute to the development of immunotherapy specifically targeting DTCs. Here we review current knowledge about systemic and site-specific immune-cancer crosstalk in the early steps of metastasis formation. Moreover, we highlight how conventional cancer therapies can shape the pre-metastatic niche enabling immune escape of newly arrived DTCs.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Julien Schaller1, Hélène Maby-El Hajjami1, Sylvie Rusakiewicz1, Kalliopi Ioannidou2, Nathalie Piazzon2, Alexandra Miles3, Déla Golshayan4, Olivier Gaide3, Daniel Hohl3, Daniel E. Speiser1 and Karin Schaeuble1 1 Department of Oncology, University Hospital Lausanne (CHUV/UNIL), Lausanne, Switzerland 2 Institute of Pathology, University Hospital Lausanne (CHUV), Lausanne, Switzerland 3 Department of Dermatology, University Hospital Lausanne (CHUV), Lausanne, Switzerland 4 Transplantation Center, University Hospital Lausanne (CHUV/UNIL), Lausanne, Switzerland Correspondence to: Karin Schaeuble, email: karin.schauble@unil.ch Keywords: lymphatic vessel; CD8+ T cell; perineural infiltration; skin squamous-cell carcinoma; tumor immunology Received: July 30, 2020 Accepted: February 26, 2021 Published: March 30, 2021 Copyright: © 2021 Schaller et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies. Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients’ prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma. <!--x2o[ca91d152]-->